Bacterial toxins cause cardiac dysfunction and death through an inflammatory process, but the mechanism remains unclear.
Simvastatin is recognized as having anti-inflammatory properties beyond its
lipid-lowering effects. We examined Staphylococcus aureus alpha-toxin in isolated heart and in vivo models and tested
simvastatin's effects in
sepsis. Isolated Langendorff-perfused rat hearts were exposed to a recirculating perfusate containing alpha-toxin (0.5 microg mL(-1)). Compared with controls, there was a significant increase in coronary perfusion pressure and fall in myocardial performance. Significant increases in p53 expression and apoptosis (1.3 +/- 0.5 to 7.1 +/- 1.4 terminal deoxynucleaotidyl
transferase nick end labeling-positive cells; P < 0.05) compared with controls were observed, but markers of
necrosis were similar. In parallel experiments, anaesthetized rats receiving alpha-toxin (40 microg kg(-1), i.v.) had in vivo hemodynamic parameters and
serum markers of
necrosis monitored for 4 h before the hearts were analyzed for histological change, p53 expression, and apoptosis. Over 4 h, alpha-toxin exposure produced substantial hemodynamic effects. In addition, p53 expression (0.2 +/- 0.2 to 7.1 +/- 0.5 p53-positive myocytes; P < 0.05),
TNF-alpha levels, the degree of apoptosis, and markers of
necrosis were all significantly increased compared with control animals. Pretreatment with
simvastatin protected against alpha-toxin-induced
sepsis associated with reduced p53,
TNF-alpha, apoptosis, and
necrosis. We found significant changes in systemic hemodynamics, coronary perfusion pressure, myocardial function, and increased p53 expression with apoptosis due to bacterial
exotoxin. In vivo changes were significantly inhibited by pretreatment with
simvastatin. We provide novel evidence for the mechanisms by which
septicemia causes myocardial depression and hint at a potential role for
simvastatin as an inhibitor of apoptosis in
sepsis.